Inflammation is a disorder, which is characterized by redness, fever, swelling and pain. Prostaglandins play a major role in the inflammation process and inhibition of prostaglandin production, especially of PGG2, PGH2 and PGE2 has been a common target to treat inflammation. However, NSAIDs that are commonly used to treat prostaglandin-induced pain and inflammation also effect other prostaglandin-regulated processes not associated with inflammation process. This leads to severe side effects including life threatening gastric ulcers dyspepsia & nephrotoxicity, thereby reducing their therapeutic use.
Previously, NSAIDs have been found to prevent the production of prostaglandins by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway, including the enzyme cyclooxygenase (COX). In early 1990s, COX was demonstrated to exist as two distinct isoforms COX-1 and COX-2 (PNAS (1991) 88, 2692-96) and recently a third isoform COX-3 has been discovered from brain (PNAS (2002) 99, 13926-13931). COX-1 & COX-2 serve different physiological and pathophysiological functions. COX-1 is the constitutive isoform & is mainly responsible for the synthesis of cytoprotective prostaglandins in the GI tract and for the synthesis of thromboxane, which triggers platelet aggregation in blood platelets. COX-2 is believed to be an inducible isoform, which is stimulated in response to endotoxins, cytokines, and mitogens. Importantly, COX-2 plays a major role in prostaglandin biosynthesis in inflammatory cells (monocytes/macrophages) and in the central nervous system. (Current Medicinal Chemistry (2000) 7, 1041-62). The use of COX-2 as anti-cancer agents is discussed in Curr Drug Targets 2001 March; 2 (1):79-106. Hence, the difference in the function of COX-1 & COX-2 provides a goal of separating the toxicity, particularly related to the gastrointestinal tract from efficacy of NSAIDs by developing drugs that are selective COX-2 inhibitors as anti-inflammatory, analgesic, and/or antipyretic agents. It is believed that these compounds would have minimum or no GI & hematologic liabilities from COX-1 inhibition that plague almost all currently marketed NSAIDs, most of which inhibit both COX-1 & COX-2, with specificity for COX-1 inhibition greatly exceeding that for COX-2 inhibition. Celecoxib and Rofecoxib were the first two selective COX-2 inhibitors approved for selected markets for the treatment of certain inflammatory conditions.
Although, the concept of selectively inhibiting COX-2 in order to have better efficacy & safety looks quite very attractive, recent clinical studies have raised doubts about the long term efficacy of selective COX-2 inhibitors. Celecoxib was not found to be any better than other NSAIDs in long-term clinical study (BMJ (2002) 324, 1287-88). On the other hand highly selective COX-2 inhibitors produce adverse cardiovascular effects that are not seen in non-selective COX inhibitors (Science (2002) 296, 539-541; JAMA (2001) 268 954-959).
The references below disclose anti-inflammatory compounds that are selective COX-2 inhibitors. Increasing number of publications & patents emerging steadily indicates continuing efforts to find a safe and effective anti-inflammatory agent. Such novel compounds, their methods for preparation are described in EP1006114, EP1099695, EP418845, EP554829, EP0863134, EP0714895, EP0799523, GB2294879, U.S. Pat. No. 5,474,995, U.S. Pat. No. 5,486,534, U.S. Pat. No. 5,510,368, U.S. Pat. No. 5,686,460, U.S. Pat. No. 5,691,374, U.S. Pat. No. 5,710,140, U.S. Pat. No. 5,723,485, U.S. Pat. No. 5,776,967, U.S. Pat. No. 5,981,576, U.S. Pat. No. 5,922,742, U.S. Pat. No. 6,083,969, U.S. Pat. No. 6,071,954, U.S. Pat. No. 6,071,936, U.S. Pat. No. 6,133,292, U.S. Pat. No. 6,143,892, U.S. Pat. No. 6,274,590, WO9415932, WO9427980, WO9500501, WO9515315, WO9515316, WO9515317, WO9515318, WO9518799, WO9603387, WO9603392, WO9606840, WO9609304, WO9610012, WO9616934, WO9619469, WO9621667, WO9623786, WO9624585, WO9625405, WO9631509, WO9636623, WO9637467, WO9638418, WO9636617, WO9703667, WO9703953, WO9713755, WO9714691, WO9716435, WO9727181, WO9734882, WO9737984, WO9746524, WO97727181, WO9804527, WO9807425, WO9807714, WO9811080 WO9813483, WO9816227, WO9821195, WO9822442, WO9825896, WO9841511, WO9841516, WO9843966, WO9852940, WO9910331, WO9910332, WO9912930, WO9915503, WO9923087, WO9935130, WO0026216, WO0052008, WO0024719, WO0134577, WO0140216.
In addition to COX, the enzyme lipoxygenase (LOX) also plays an important role in inflammation, 5-LOX products such as LTB4, LTC4 and LTD4 are involved in a variety of pathological processes (Pharmacol Rev (2003), 55 195-227). Therefore, inhibition of 5-LOX activity may produce beneficial effects in inflammation. Studies have indicated that dual inhibitors of COX and LOX may have better safety profile (Pharmacol Res (2001), 43 429-436) than non-selective NSAIDs. The compounds of the present invention are useful in treating inflammatory conditions caused by increased activities of COX and/or LOX enzymes.
Cytokines are known to be involved in inflammatory processes. Tumor necrosis factor α(TNF-α) is described as a key proinflammatory mediator in autoimmune diseases. This 26 kDa enzyme is membrane associated until processed into a smaller (17 kDa) soluble form by TNF-α converting enzyme (TACE). The compounds of the present invention are also useful in the treatment of inflammatory diseases such as arthritis by inhibiting TNF-α, or TACE or by inhibiting the production of Tumor necrosis factor-α.